Asthma affects 300 million people worldwide. Since asthma is a heterogeneous disorder driven by concerted effects of multiple cytokines produced in response to inflammatory stimuli, characterization of the proportional contribution, functional importance and relevance of individual cytokines in asthma pathogenesis is necessary to develop better strategies for therapeutic intervention. The objective of this project is to generat mice deficient in the cytokines IL-1F6 (IL-36), IL-1F9 (IL-36?) and their receptor IL-1RL2 (IL-36R), and perform proof-of-concept studies to determine if individual or collective deficiency of these cytokines attenuates asthma in murine models. IL-1F6 and IL-1F9 are novel cytokines that possess structural and functional similarity to classical IL-1 molecules (IL-1, IL-1), but bind to a novel receptor IL-1RL2 instead of the classical IL-1 receptor IL-1R1. We and others have reported that IL-1F6 and IL-1F9 are expressed predominantly in airway epithelial cells. Recent reports have demonstrated that IL-1RL2, the receptor for these cytokines, is expressed in bone marrow derived dendritic cells and CD4+ lymphocytes, cell types that play a critical role in asthma pathogenesis. We have previously shown that IL-1F9 is upregulated in the lungs of allergen challenged mice and intratracheal administration of recombinant IL-1F9 induced proinflammatory chemokine production, Nuclear factor kappa B (NF-?B) activation and neutrophil influx in the lungs of mice. In addition, IL-1F6 and IL- 1RL2 exert proinflammatory effects in the development of skin inflammation and psoriasis. While such accumulating evidence emphasizes the importance of these novel cytokines in inflammatory diseases, the exact role of endogenously produced IL-1F6, IL-1F9 and IL-1RL2 in the context of inflammation is still uncharacterized due to the lack of commercially available IL-1F6, IL-1F9 and IL-1RL2 deficient mice. Therefore, the proposed studies will generate novel reagents to clarify the functional impact of IL-1F6, IL-1F9 and IL-1RL2 in murine models of asthma. These studies will pave way for future investigation of regulatory mechanisms mediated by these novel cytokines that may be of potential therapeutic importance in human asthma and other inflammatory lung diseases. PUBLIC HEALTH RELEVANCE: Due to the complexity of asthma as a disease, novel therapies remain elusive. Identification and characterization of novel endogenous mediators that regulate asthma pathogenesis is essential to gain a better understanding of potential therapeutic intervention points during the onset and persistence of asthma. This application seeks to perform reagent generation and pilot studies to characterize the role of novel Interleukin-1 (IL-1) like cytokines and their receptors (IL-1F6, IL-1F9 and IL-1RL2) in asthma pathogenesis. Results from this study will provide critical insights into the functional relevance and therapeutic potential of these cytokines in asthma.